Targeted Mutations in ATR Pathway and Implications for Combination Strategies

Many chemotherapy agents work by causing DNA strand breaks or accumulation of DNA replication intermediates. ATR (ataxia-telangiectasia mutated and Rad 3-related protein) is a potential target for combination drug strategies, because signaling of this protein in response to such altered DNA structures results in activation of cellular survival mechanisms.

In a recent study, Wilsker and colleagues from the Johns Hopkins University School of Medicine, Baltimore, used a panel of genetically modified human cancer cells to identify the roles of upstream and downstream components of the ATR pathway in the responses to common therapeutic agents. It was found that activation of the upstream kinase S-phase–specific cyclin-dependent kinase (Cdk) 2 was required for robust activation of ATR in response to numerous and diverse chemotherapeutic agents, and that Cdk2-mediated ATR activation promoted cell survival after treatment with many drugs. In contrast, downstream signaling from ATR directly to the checkpoint kinase Chk1 was required for survival responses for a smaller subset of the drugs tested.

Enhanced Therapeutic Effects

These findings indicate that specific inhibition of the Cdk2/ATR/Chk1 pathway with distinct regulating agents could differentially sensitize cancer cells to a wide range of therapeutic agents. As the investigators stated, “ATR is known to be activated by a broad range of agents that directly or indirectly inhibit DNA replication. Our study of a large panel of approved anticancer agents shows just how broad this range can be and how seemingly disconnected pathways can affect DNA metabolism.”

In this regard, they noted that dactinomycin and bortezomib (Velcade), for example, induced a similar dependence on ATR pathways for cell growth after treatment, despite having highly dissimilar mechanisms of action—a finding suggesting that “there may be many avenues by which ATR inhibitors might provide enhanced therapeutic effects.” A number of ATR inhibitors currently are in preclinical evaluation. The investigators suggested that, on the basis of findings in their study, “If these inhibitors prove to be sufficiently specific, they may facilitate many potential combinatorial strategies that may be broadly applicable to many types of cancer.” ■